Microglia activity modulated by T cell Ig and mucin domain protein 3 (Tim-3)

• Microglia upregulate Tim-3 expression upon inflammatory or injury insults.
• Tim-3 activation regulates inflammatory mediators in microglia.
• Tim-3 mediates microglial toxicity to neurons.
• Tim-3 modulates the differentiation of NG2 cells into oligodendrocytes.
• Tim-3 activation triggers phosphorylation of ERK1/2 and JNK but not p38 and NF-κB pathways.

Microglia are the main innate immune cells in the central nervous system that are actively involved in maintaining brain homeostasis and diseases. T cell Ig and mucin domain protein 3 (Tim-3) plays critical roles in both the adaptive and the innate immune system and is an emerging therapeutic target for treatment of various disorders. In the brain Tim-3 is specifically expressed on microglia but its functional role is unclear. Here, we showed that Tim-3 was up-regulated on microglia by ATP or LPS stimulation. Tim-3 activation with antibodies increased microglia expression of TGF-β, TNF-α and IL-1β. Blocking of Tim-3 with antibodies decreased the microglial phagocytosis of apoptotic neurons. Tim-3 blocking alleviated the detrimental effect of microglia on neurons and promoted NG2 cell differentiation in co-cultures. Finally, MAPKs namely ERK1/2 and JNK proteins were phosphorylated upon Tim-3 activation in microglia. Data indicated that Tim-3 modulates microglia activity and regulates the interaction of microglia–neural cells.